Dimethyl itaconate inhibits LPS-induced inflammatory release and apoptosis in alveolar type II epithelial and bronchial epithelial cells by activating pulmonary surfactant proteins A and D.

BACKGROUND: Injury to the lung is a common, clinically serious inflammatory disease. However, its pathogenesis remains unclear, and the existing treatments, including cytokine therapy, stem cell therapy, and hormone therapy, are not completely effective in treating this disease. Dimethyl itaconate (DMI) is a surfactant with important anti-inflammatory effects. OBJECTIVE: The present study used alveolar type II (AT II) and bronchial epithelial cells as models to determine the role of DMI in lung injury. MATERIAL AND METHODS: First, the effects of DMI were established on the survival, inflammatory release, and apoptosis in lipopolysaccharide (LPS)-induced AT II and bronchial epithelial cells. The association between DMI and Sirtuin1 (SIRT1) was assessed using molecular docking. Next, by constructing interference plasmids to inhibit surfactant protein (SP)-A and SP-D expressions, the effect of DMI was observed on inflammatory release and apoptosis. RESULTS: The results revealed that DMI increased the survival rate and expression levels of SP-A, SP-D, and SIRT1, and inhibited inflammatory factors as well as apoptosis in LPS-induced cells. Furthermore, DMI could bind to SIRT1 to regulate SP-A and SP-D expressions. After SP-A and SP-D expressions were inhibited, the inhibitory effect of DMI was reversed on inflammatory release and apoptosis. CONCLUSION: The findings of the present study revealed that DMI inhibited LPS-induced inflammatory release and apoptosis in cells by targeting SIRT1 and then activating SP-A and SP-D. This novel insight into the pharmacological mechanism of DMI lays the foundation for its later use for alleviating lung injury.

[Efficacy and safety of levetiracetam versus phenytoin as second-line drugs for the treatment of children with convulsive status epilepticus: a Meta analysis].

OBJECTIVE: To systematically evaluate the efficacy and safety of levetiracetam (LEV) versus phenytoin (PHT) as second-line drugs for the treatment of convulsive status epilepticus (CSE) in children. METHODS: English and Chinese electronic databases were searched for the randomized controlled trials comparing the efficacy and safety of LEV and PHT as second-line drugs for the treatment of childhood CSE. RevMan 5.3 software was used for data analysis. RESULTS: Seven studies with 1 434 children were included. The Meta analysis showed that compared with the PHT group, the LEV group achieved a significantly higher control rate of CSE (RR=1.12, 95%CI:1.00-1.24, P=0.05), but there was no significant difference between the two groups in the recurrence rate of epilepsy within 24 hours (RR=0.82, 95%CI:0.22-3.11, P=0.77) and the rate of further antiepileptic drug therapy (RR=0.97, 95%CI:0.64-1.45, P=0.87). There was no significant difference in the incidence rate of adverse events between the two groups (RR=0.77, 95%CI:0.55-1.09, P=0.15). CONCLUSIONS: LEV has a better clinical effect than PHT in the treatment of children with CSE and does not increase the incidence rate of adverse events.

[Levels of intracellular IL-6 and IFN-gamma in children with acute lymphoblastic leukemia].

OBJECTIVE: To study the changes of intracellular interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) expressions in children with acute lymphoblastic leukemia (ALL) at different stages, and to examine the correlation between IL-6 and IFN-gamma in ALL children. METHODS: The levels of intracellular IL-6 and IFN-gamma in venous blood lymphocytes were detected by flow cytometry in 42 children with ALL at diagnosis and at remission stage. Twenty healthy children were used as the controls. RESULTS: The intracellular IL-6 level in ALL children at diagnosis was 81.74+/-9.31, which was much higher than that in the Control group (5.67 +/- 0.96 ) (P < 0.01). The intracellular IFN-gamma level in ALL children (1.31 +/- 0.32) was significantly lower than that in the Control group (1.46 +/- 0.49) (P < 0.01). However, the intracellular IL-6 level (27.52 +/- 3.40) decreased remarkably in ALL patients at remission stage (P < 0.01), but was still higher than that in the Control group (P < 0.01). In contrast, the intracellular IFN-gamma level (1.97 +/- 0.72) increased noticeably in ALL patients at remission stage, which was higher than that at diagnosis and the Control group (P < 0.01). A negative correlation was found between the intracellular IL-6 and the IFN-gamma levels in ALL patients (r=-0.476, P < 0.05). CONCLUSIONS: Intracellular IL-6 and IFN-gamma levels may be used as the markers for monitoring the response to treatment in ALL patients. There is a negative correlation between intracellular IL-6 and IFN-gamma levels in ALL children.

[Localized expressing tendency of nuclear transcription factor kappa-B, pro-fibrosis genetic factors and fibronectin mRNA in renal tissues in proteinuria overload nephrotic young rats].

OBJECTIVE: Terminal stage renal failure is the final common fate of chronic nephropathies independent of the type of initial insult. Abnormally filtered proteins have an intrinsic renal toxicity linked to their over-reabsorption by proximal tubular cells and activation of tubular-dependent pathways of interstitial inflammation and fibrosis. The functional importance of tubulointerstitial events in progressive renal disease is supported by evidence that the severity of tubular interstitial damage strongly correlates with the risk of renal failure. The present study aimed to investigate the expressive tendency of some pro-fibrosis genetic factors mRNA, including thrombospondin-1 (TSP-1), transforming growth factor-beta1 (TGF-beta1), connective tissue growth factor (CTGF) and the major component of extracellular matrix-fibronectin (FN) in renal tissues at different time points during early stage of renal lesions caused by proteinuria in bovine serum albumin (BSA) injection-induced proteinuria overload nephrotic young rats and the significance of these factors on tubulointerstitial fibrosis development. METHODS: Female young Wistar rats aged 3-4 weeks with proteinuria overload nephrosis induced by BSA (1.0 g/d) injected intraperitoneally were used as experimental models. The 80 young rats were divided into control group (n = 40) and BSA injected group (n = 40). At different time points (weeks 1, 2, 3 and 4), the urinary protein was measured by Coomassie brilliant blue colorimetric assay; the renal tissues morphologic changes were evaluated after HE staining; the P(65)/Rel-A, TSP-1, TGF-beta1 and CTGF mRNA expression in renal tissues was determined by in situ hybridization method and the FN mRNA expression was detected by Northern blot. The experimental data were evaluated by statistics software SPSS10.0. RESULTS: (1) Three to four weeks after BSA injection, heavy proteinuria was observed in the rats of BSA group (week 3: 104.3 +/- 21.8 mg/24 h; week 4: 131.1 +/- 18.3 mg/24 h). The proteinuria deteriorated progressively afterwards. Histopathological examination revealed that inflammatory cells infiltrated into tubulointerstitial areas extensively, protein casts were seen in tubules and edema occurred in tubulointerstitial areas. (2) In situ hybridization showed that NF-kappaB (P(65)/Rel-A) mRNA expression was up-regulated progressively in nuclei of tubular epithelial cells, the semi-quantitative scores (at 1, 2, 3 and 4 weeks) were 2.33 +/- 0.20, 2.76 +/- 0.12, 2.96 +/- 0.19, and 3.76 +/- 0.18, respectively (F = 37.34, P < 0.01). (3) At 1 week after BSA injection, the TSP-1 mRNA expression appeared in glomeruli and increased, but was light in tubulointerstitial areas, its expressive peak was observed at week 2, and declined to mild after weeks 3 and 4. The semi-quantitative scores at different time points suggested that TSP-1 mRNA was expressed mainly in early stage of lesion in this model, then, this tendency turned to a flat roof smoothly. (4) TGF-beta1 and CTGF mRNA was up-regulated simultaneously in tubular epithelial cells (F = 8.80, P < 0.01 F = 19.41, P < 0.01). (5) Northern blotting showed that FN mRNA was considerably up-regulated at second week in the kidneys of rats in BSA group, 2.7-fold higher at week 4 than that at week 1 in BSA group rats, and was 3.6-fold higher than that of control group. CONCLUSION: The present study suggested that NF-kappaB (P(65)/Rel-A) mRNA expression and its activity was enhanced significantly by proteinuria-loading and synchronized with high expression of TSP-1, TGF-beta1, and CTGF mRNA in the kidney, at the same time, FN mRNA was up-regulated in renal tissues and an aggravating tendency in tubulointerstitial lesions was observed in nephrotic young rats with heavy proteinuria.